The transport of non-ferrous divalent metals, such as zinc, copper, nickel and cadmium in serum is not well-understood. This lack of information hampers the diagnosis and treatment of states of altered metal metabolism, of deficiencies in essential metals like zinc and copper, and of toxic effects of metals like cadmium. The long-term objective of this research is to achieve a more complete understanding of the physiological and pathological mechanisms of metal and organic ion transport and homeostasis, especially in the perinatal period, and thus make possible improved clinical diagnosis and therapy. A recently described serum protein, 3.8 S alpha 2-histidine-rich glycoprotein (HRG), binds divalent metal ions, like cadmium, copper and zinc with high affinity and also binds organic ions like heme with a lower but still significant affinity. In addition, the serum concentration of HRG declines in women during pregnancy to a level that is only 50% that of healthy adult women. These observations suggest that HRG may have an important role in the homeostasis or transport of metal ions in serum and in providing essential metal nutrients to the fetus. We propose to study this protein using three basic approaches. First, we will continue to determine the serum concentrations of HRG in pregnancy and in a variety of disease states to provide information on its function and to evaluate its diagnostic potential. Second, we will characterize the physical-chemical properties of HRG with special emphasis on its interactions with metals and the residues of the protein that contribute to this function. Third, we will develop an animal model to enable us to pursue metabolic studies of HRG in pregnancy and in aberrant states of metal metabolism. Immunological methods are being developed for the specific identification and quantitation of protein-metal complexes in serum. This information is expected to contribute to understanding of HRG's function, of the transport of metals in serum, and of nutritional needs in the perinatal period.